Certain aryl and hetero aryl oximes and 4-benzoyloxycyclohexanone oxime



United States Patent 3,481,944 CERTAIN ARYL AND HETERO ARYL OXIMES AND4-BENZOYLOXYCYCLOHEXANONE OXIME Aram Mooradian, Schodack, N.Y., assignorto Sterling Drug Inc., New York, N.Y., a corporation of Delaware N0Drawing. Application May 9, 1967, Ser. No. 637,056, which is acontinuation-in-part of application Ser. No. 596,395, Nov. 23, 1966.Divided and this application Nov. 1, 1968, Ser. No. 772,823

Int. Cl. C07d 31/42; C07c 131/00 US. Cl. 260296 2 Claims ABSTRACT OF THEDISCLOSURE Benzofurans are prepared by heating above approximately 50 C.and O-phenyl ketoxime in an acidic medium where the O-phenyl group isunsubstituted at one position ortho to the position containing theO-linkage and is substituted at either one or both of the paraand otherortho-positions by an electron withdrawing group. The benzofurans havepharmacological properties, e.g., antiinflammatory activity, andchemotherapeutic properties, e.g., antibacterial activity.

This invention relates to a novel process for preparing benzofurans andto compositions used and prepared therein.

This application is a division of application Ser. No. 637,056, filedMay 9, 1967, which in turn is a continuation-in-part of copendingapplication Ser. No. 596,395, filed Nov. 23, 1966, now abandoned.

The invention sought to be patented, in its process aspect, resides inthe process for producing a benzofuran which comprises heating aboveapproximately 50 C. an O-phenyl ketoxime in an acidic medium where theO- pheny group is unsubstituted at one position ortho to the positioncontaining the O-linkage and is substituted at either one or both of theparaand other orthopositions by an electron withdrawing group, e.g.,nitro, trihalomethyl, carbo-(lower-alkoxy), carboxy, cyano, loweralkanoyl, phenylsulfonyl and N,N di (loweralkyl)sulfamyl. Preferredketoximes because of their ready availability are O-phenyl ketoximes oflow-molecular weight ketones, e.g., a di-(lower-alkyl) ketone, acyclohexanone, a lower-alkyl phenyl ketone or a loweralkyllower-ketoalkanoate. A variation of the process aspect of the inventionresides in the process which comprises heating in an acidic medium anO-(2-pyridyl)cyclohexanone oxime to form a 5,6,7,8 tetrahydrobenzofuro-[2,3 b] pyridine. The benzofurans produced by the process of theinvention posses the inherent applied use characteristics of havingpharmacological properties, e.g., antiinfiammatory activity, asdetermined by standard pharmacological evaluation procedures and ofhaving chemotherapeutic properties, e.g., antibacterial activity, asdetermined by standard chemotherapeutic evaluation procedures. Also,they are useful as intermediates for the preparation of otherbenzofurans having pharmacological or chemotherapeutic properties.

The invention sought to be patented, in one composition aspect, residesin 4-benzoyloxycyclohexanone oxime which was found, in addition to beinguseful as an intermediate in the preparation of O-phenyl oximes, topossess the inherent applied use characteristics of havingpharmacological properties, e.g., antiinflammatory activity.

Another composition aspect of the invention sought to be patentedresides in the intermediates: O-(6 chloro- 2 pyridyl)cyclohexanoneoxime, 4 [nitrophenoxy)- imino1cyclohexyl benzoate, O (4 N,NdimethylsulfamylphenyDacetophenone oxime, O (4 phenylsulfonylphenyl)acetone oxime, O-(4-N,N-dimethylsulfamylphenyl)-4-methoxyacetophenoneoxime (also has antibacterial activity), O-(4-cyanophenyl)acetone oxime,and O-(4- acetylphenyDacetone oxime, the last two compounds also havingantiiflammatory activity.

The invention sought to be patented, in another composition aspect,resides in the following benzofurans: ethyl 2 methyl 5 nitro 7benzofurancarboxylate, 2- methyl 7 nitro 5 trifluoromethylbenzofuran, 2-methyl 5 nitro 7 trifluoromethylbenzofuran, 2- methyl 5trifluoromethylbenzofuran, 5 acetamido 2- methylbenzofuran, 5 cyano 2methylbenzofuran, 2- phenyl 5 trifiuoromet-hylbenzofuran, 2 phenyl 7-trifluoromethylbenzofuran, N,N, dimethyl 2 phenyl- 5benzofuransulfonamide, N,N, dimethyl 2 (4- methoxyphenyl) 5benzofuransulfona'mide, ethyl 2- methyl 5 nitrobenzofuran 3 acetate, 2benzoyloxyl,2,3,4 tetrahydro 8 nitrodibenzofuran, 2 chloro- 5,6,7,8tetrahydrobenzofuro[2,3-b]pyridine, 2-methyl-5-phenylsulfonylbenzofuran, ethyl 2 phenyl 5 benzofurancarboxylate, ethyl2 (4 methoxphenyl) 5 benzofurancarboxylate, and 2 diethylaminoethyl 2(4- methoxyphenyl) 5 benzofurancarboxyl-ate. These novel compounds,which are produced by the process of the invention, possess the inherentapplied use characteristics of having pharmacological properties, e.g.,antiinfiammatory activity, as determined by standard pharmacologicalevaluation procedures and, also, of having chemotherapeutic properties,e.g., antibacterial activity, as determined by standard chemotherapeuticevaluation procedures.

The term lower-alkyl, as used throughout this specification, means analkyl radical having from one to six carbon atoms inclusive, illustratedby methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, isobutyl,n-amyl, nhexyl, and the like.

The term lower-alkoxy, as used throughout this specification, means :analkoxy radical having from one to six carbon atoms inclusive, illustrateby methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy,isobutoxy, nhexoxy, and the like.

The term lower-ketoalkanoate, as used throughout this specification,means a keto-alkanoate ester moiety derived from a keto-allcanoie acidhaving from three to six carbon atoms, said lower-ketoalkanoateillustrated by pyruvate, acetoacetate and levulinate.

The manner and process of making and using the instant invention willnow be generally described so as to enable a person skilled in the artof chemistry to make and use the same, as follows:

Preparation of intermediate O-phenyl ketoximes. These intermediates,some of which are known and some of which are novel, are prepared byreacting a metal salt of the ketoxime in a suitable solvent, e.g.,dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide ordimethylacetamide, with an ortho-substitutable active phenyl halide,i.e., a phenyl halide where phenyl is unsubstituted at one orthoposition and is substituted at either one or both of the para and theother ortho positions by a low molecular electron withdrawing group, asillustrated above. The reaction is usually exothermic and is carried outby mixing the reactants in the solvent with stirring and then stirringthe reaction mixture until the reaction is complete. Gentle heating, upto about 50 to 0, might be necessary to start the reaction in someinstances wherein gentle heating is then continued to ensure completionof the reaction. Alkali metal salts of the oximes are preferred becauseof their ready availability and ease of preparation by generally knownprocedures, e.g., by reacting sodium hydride or potassium alkoxide withthe oxime. The corresponding O-(2- pyridyl)cyclohexanone oximes areprepared by the above procedure using a 2-halopyridine and a metal saltof cyclohexanone oxime.

Conversion of O-phenyl oximes to benzofurans-This novel rearrangementconversion is carried out by heating above approximately 50 C. theO-phenyl oxime in an acidic medium, preferably a strong inorganic acid,e.g., hydrogen chloride, hydrogen bromide, in a suitable solvent, e.g.,a lower-alkanol, a lower-alkanecarboxylic acid of two to four carbonatoms, and the like; a preferred solvent is ethanol. A preferredlower-alkanecarboxylic acid solvent is acetic acid. The rearrangementconversion can also be run in a lower-halogenated-alkanoic acid, e.g.,trifiuoroacetic acid, which acts both as acid and solvent. The reactionis conveniently effected by refluxing the O-phenyl oxime in ethanolichydrogen chloride from about one to four hours. The reaction also wasfound to take place at lower temperatures, down to about 50 C., butrequiring a longer reaction period; higher temperatures, up to about100-125 C. or higher, can be used but to no particular advantage. In anyevent, it will be obvious that the reaction temperature should be belowthat which would result in any significant decomposition of thereactants or final products. Below 50 C., benzofuran formationordinarily does not take place in sufii-- cient degree to affordpractical yields.

Modifications of the foregoing process will be apparent to a chemistskilled in the art. For example, in place of hydrogen chloride, hydrogenbromide or trifiuoroacetic acid, there can be used other stronginorganic acids, e.g., hydrogen iodide, hydrogen fluoride, sulfuricacid, boron trifluoride etherate, and the like, or strong organic acids,e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, and the like. Also, other solvents can be used, e.g.,tetrahydrofuran, dioxane, and the like.

For purpose of illustration but without limiting the generality of theforegoing, the conversion is illustrated for preferred embodiments asfollows:

(II) where at least one of Q and Q is a low-molecular weight electronWithdrawing group, e.g., nitro, trihalomethyl, carbo-(lower-alkoxy),carboxy, cyano, lower-alkanoyl, phenylsulfonyl, andN,N-di-(lower-alkyl)sulfamyl, and the other one of Q and Q is hydrogen,said electron withdrawing group or another low-molecular group asillustrated below; R is lower-alkyl or phenyl; R is hydrogen, alkylhaving from one to five carbon atoms or CH COO-(lower-alkyl); or, R andR are attached to form together with the 2- and 3-carbon atoms of thebenzofuran ring a tetrahydrobenzo ring. Variations of the abovepreferred structures of Formulas I and II encompassed in the process ofthe invention will be apparent to the skilled chemist, e.g., thepresence of one or more other low-molecular substituents, e.g.,lower-alkyl, halo, lower-alkoxy, lower-alkylmercapto,lower-alkylsulfonyl, di-(lower-alkyl)amino, and the like, in availableringpositions of the phenyl (R or benzenoid ring; the use ofO-(Z-pyridyl) groups in place of O-phenyl, said 2-pyridyl beingunsubstituted or hearing at ring-positions 4, 5 and 6 one or more saidlow-molecular weight substituents; and, the use of other low-moleculargroups for R and R Illustrative conversions of the foregoing are:2-methyl-S-nitrobenzofuran from O-(4-nitrophenyl)acetone oxime;S-nitro-2-phenylbenzofuran from O-(4-nitrophenyl)acetophenone oxime;ethyl 2-methyl-5 nitro 7- benzofurancarboxylate from"O-(2-carboxy-4-nitrophenyl) acetone oxime; 2-methyl-7.-nifro5trifiuoromethylbenzotu an f om Q-( -nitro 4 trltluorome hy ph y )ace onoxime; 5-cyano-2-methylbenzofuran from O-(4 cyanophenyl)acetone oxime;N,N-dimethyl-2-phenyl-5 benzofuransulfonamide fromO-(4-N,N-dimethylsulfamylphenyl)acetophenone oxime;1,2,3,4-tetrahydro-8-nitrodibenzofuran fromO-(4-nitrophenyl)cyclohexanone oxime; 2- benzoyloxy-l,2,3,4-tetrahydro-8nitrodibenzofuran from 4- (4-nitrophenoxy imino] cyclohexyl benzoate;2chloro- 5,6,7,8 tetrahydrobenzofuro[2,3-b] pyridine from O-(5chloro-Z-pyridylcyclohexanone oxime; a mixture of 2,3-dimethyl-S-nitrobenzofuran and 2-ethyl-5-nitrobenzofuran fromO-(4-nitrophenyl) 2- buianone oxime; and, ethyl2-methyl-5-nitrobenzofuran-3-acetate from tert-butyl O-(4-nitrophenyl)levulinate oxime.

The molecular structures of the O-phenyl oximes and benzofurans wereassigned on the basis of stud of their infrared and NMR spectra, andconfirmed by the correspondence of calculated and found values for theelementary analyses for representative examples.

The best mode contemplated for carrying out the invention will now beset forth as follows:

(A) PREPARATION OF O-PHENYL OXIMES (l) O-(4-nitrophenyl)acetone oxime-Toa solution of 3.65 g. of acetone oxime in 125 ml. of dimethyl sulfoxidewas added 2.15 g. of a 56% dispersion of sodium hy dride in mineral oil.The resulting mixture was stirred for fifteen minutes and then there wasadded 10.1 g. of 4-bromonitrobenzene. After the subsequent exothermicreaction and bubbling had subsided, the reaction mixture was poured intowater and the resulting brown precipitate was collected. The solid wassuspended in alcohol and water added to the suspension. The solid thatseparated was collected, dried an recrystallize from isopropyl alcoholto yield 4.9 g. of O-(4-nitrophenyl)acetone oxime, M.P. 104-106 C.

(2) O-(2,4-dinitrophenyl)acetone oxime, M.P. 8791 C., was preparedfollowing the procedure of Example A(1) by reacting the sodium salt ofacetone oxime and 2,4-dinitrochlorobenzene in tetrahydrofuran for twohours.

(3) O-(4-nitrophenyl)acetophenone oxime, M.P. 122- 124 C., was preparedas in Example A(1) by refluxing the sodium salt of acetophenone oximeand 4-nitrofluorobenzene in tetrahydrofuran for ten hours.

(4) O-(2-nitrophenyl)acetone oxime, M.P. 5659 C., was prepared as inExample A(1) by stirring the sodium salt of acetone oxime and2-nitrobromobenzene in dimethyl sulfoxide for forty-five minutes.

(5) 0-(2-carboxy-4-nitrophenyl)acetone oxime.--To a solution of 20.1 g.of 2-chloro-5-nitrobenzoic acid in 250 ml. of tetrahydrofuran was addedwith stirring 4.27 g. of a 56.2% dispersion of sodium hydride in mineraloil. Sufficient dimethyl sulfoxide was added to the suspension to effectdissolution. A solution of 7.3 g. of acetone oxime in ml. oftetrahydrofuran was heated with 4.27 g. of 56.2% sodium hydride followedby addition of 50 ml. of dimethyl sulfoxide. The mixture was heated withstirring'until evolution of hydrogen had ceased (about fifteen minutes)and then poured into the solution of the benzoic acid salt. Theresulting suspension was first stirred at room temperature for aboutforty-five minutes and then heated at reflux for about ninety minutes.The reaction mixture was next treated with water and the tetrahydrofuranwas removed by distilling in vacuofThe remaining aqueous layer wasextracted with n-pentane to remove the mineral oil, treated withdecolorizing charcoal and filtered, and the filtrate acidified with 10%aqueous hydrochloric acid. The solid that separated was collected andrecrystallized from ethyl acetate to yield 16.0 g. ofO-(2-carboxy-4-nitrophenyl)acetone oxime, M.P. 169-171" C. (withdecomposition).

(6) O-(2-nitro-4-trifluoromethylphenyl)acetone oxime, M.P. 52-55 C., wasprepared as in Example A(1) by stirring at room temperature for one hourthe sodium salt of acetone oxime and 4-chloro-3-nitrobenzotrifiuo: ridein dimethyl sulfoxide. After pouring the reaction mix ture into ice andwater, the product was obtained by extracting with ether, evaporating011 the ether, and recrystallizing from ethanol and then from n-hexane.

(7) O (4-trifluoromethylphenyl)acetone oxime.To 200 ml. of drydimethylformamide was added 7.3 g. of acetone oxime and 11.2 g. ofpotassium tertiary-butoxide. The resulting mixture was stirred for a fewminutes and then there was added 16.4 g. of 4-fiuorobenzotrifluoride andthe reaction mixture was heated with stirring for three hours on a steambath. It was then poured into water whereupon the crystalline productseparated. The product was collected and recrystallized from n-pentane,using decolorizing charcoal, to yield 12.6 g. ofO-(4-trifiuoromethylphenyl)acetone oxime, M.P. 4649 C.

(8) O-(4-cyanophenyl)acetone oxime, M.P. 100-103 C., was prepared as inExample A(6) by stirring at about 5060 C. for one hour a mixture of thepotassium salt of acetone oxime (using potassium tertiary-butoxide) and4- fluorobenzonitrile in dimethyl sulfoxide. When tested forantiinflammatory activity by the standard evaluation procedure ofinhibiting carrageenin-induced local foot edema in fasted rats,O-(4-cyanophenyl)acetone oxime was found to cause 28% inhibition at 100mg./kg. orally.

(9) O-(4-nitrophenyl)cyclohexanone oxime-To a solution of 17 g. ofcyclohexanone oxime in 100 ml. of dimethyl sulfoxide and 300 ml. oftetrahydrofuran was added 6.45 g. of a 56% solution of sodium hydride inmineral oil. This mixture was stirred until most of the bubblingsubsided and then there was added 23.7 g. of 4- chloronitrobenzene.After the reaction mixture had been stirred for an additional six hoursat room temperature, the tetrahydrofuran was then removed by distillingin vacuo and water was added to the residue. The crystalline product wascollected and recrystallized twice from isopropyl alcohol to yield 12.5g. of O-(4-nitrophenyl)cyclohexanone oxime, M.P. 99-101 C.

(10) 0- (6-chloro-2-pyridyl)cyclohexanone oxime. To 15.8 g. ofcyclohexane oxime in 100 ml. of dimethyl sulfoxide was added 15.7 g. ofpotassium tertiarybutoxide and 22 g. of 2,6-dichloropyridine. Theresulting mixture was stirred for one hour, then poured into water withstirring, and the mixture was stirred until the oil that separatedsolidified. The solid was collected and dissolved in hot n-hexane. Thehot hexane solution was treated with decolorizing charcoal and filtered.Removal of the hexane by distilling in vacuo gave 16.0 g. of crudeproduct. Recrystallization of 14.0 g. of this product from n-hexane andsubsequent purification by passing an ether solution of the crystalsthrough a column of aluminum oxide and elution of the column with ethergave 8.8 g. of white crystalline product which was furtherrecrystallized twice from isopropyl alcohol to yield 4.6 g. of whitecrystalline product O-(6-chloro-2-pyridyl)cyclohexane oxime, M.P. 79-81C.

(11) 4-[(4 nitrophenoxy)imino]cyclohexyl benzoate, M.P. 123125.0 C., wasprepared as in Example A(6) by reacting the potassium salt of4-benzoyloxycyclohexanone oxime and 4-fluoronitrobenzene indimethylacetamide for about fifteen minutes.

The above intermediate 4-benzoyloxycyclohexanone oxime was prepared asfollows: A reaction mixture containing 43.6 g. of4-benzoyloxycyclohexanone, 15.3 g. of hydroxylamine hydrochloride and150 ml. of pyridine was heated on a steam bath for four hours and thenpoured into one liter of water. The oil that separated was extractedwith ether. The ether extract was washed with water, dried overanhydrous magnesium sulfate and calcium sulfate, treated withdecolorizing charcoal and filtered, and the ether removed by vacuumdistillation. The aqueous layer was removed by decantation and theremaining oil was washed several times with water whereupon the oilsolidified. The solid was collected, washed with water, dried in avacuum oven at 45 for two hours, and recrystallized twice from ether toyield 26 g. of crystalline 4-benzoyloxycyclohexanone oxime,

M.P. 106108 C. 4-benzoyloxycyclohexanone oxime was found to cause 32%inhibition of carrageenin-induced local foot edema in fasted rats at 100mg./kg. orally.

(12) O-(4-nitrophenyl)-2-butanone oxime, M.P. 41- 42 C., prepared as inExample A(6) by stirring a mixture of the sodium salt of 2-butanoneoxime and 4- fiuoronitrobenzene in tetrahydrofuran for two hours.

13) O-(4-trifiuoromethylphenyl) acetophenone oxime, M.P. 9497 C., wasprepared as in Example A(1) by refluxing for three hours a mixture ofthe sodium salt of acetophenone oxime and 4-fluorobenzotrifluoride in amixture of tetrahydrofuran and dimethyl sulfoxide. I (14)O-(2-chloro-4-nitrophenyl)acetone oxime, M.P. 117-119 C., was preparedas in Example A(1) by heat- .ing on a steam bath for six hours a stirredmixture of the potassium salt (using potassium tert-butoxide) of acetoneoxime and 3,4-dichloronitrobenzene in dimethylformamide.

(15) 0 (4 N,N dimethylsulfamylphenyl)acetophenone oxime, M.P. 9597 C.,was obtained as in Example A(6) by stirring with no external heating fortwo hours a mixture of the sodium salt of acetophenone oxime andN,N-dimethyl-4-fluorobenzenesulfonamide in a mixture of tetrahydrofuranand dimethyl sulfoxide. The oxime product was recrystallized from ether.

(16) O (4 carbethoxyphenyl)acetophenone oxime, M.P. 5254 C., fromn-heptane, was prepared as in Example A(1) by heating on a steam bathwith stirring for two hours the sodium salt of acetophenone oxime andethyl 4-fluorobenzoate in a mixture of tetrahydrofuran and dimethylsulfoxide.

(l7) O-(4-acetylphenyl)acetone oxime, M.P. 5053 C., from n-hexane, wasprepared as in Example A(7) by stirring at room temperature for threehours the potassium salt of acetone oxime and 4-fluoroacet0phenone indimethyl sulfoxide. O-(4-acetylphenyl)acetone oxime, when tested in ratsfor antiinflammatory activity by the procedure referred to in ExampleA(8) was found to cause 44% inhibition at rug/kg. orally.

(18) O-(4-phenylsulfonylphenyl)acetone oxime, M.P. -134 C., fromisopropyl alcohol, was prepared as in Example A( 1) by mixing withstirring the sodium salt of acetone oxime and 4-fiuorophenyl phenylsulfone in a mixture of tetrahydrofuran and dimethyl sulfoxide andallowing the reaction mixture to stand at room temperature for threedays.

(19) O-(4-N,N dimethylsulfamylphenyl)-4-methoxy ,acetophenone oxime,M.P. 137 C., from ethanol, was prepared as in Example A(1) by heating ona steam bath for two hours a stirred mixture of the sodium salt of4-methoxyacetophenone oxime and N,N-dimethyl-4- fluorobenzenesulfonamidein a mixture of tetrahydrofuran and dimethyl sulfoxide.O-(4-N,N-dimethylsulfamylphenyl)-4-methoxyacetophenone oxime was foundto have in vitro bacteriostatic activity against Pseudomonas aeruginosaat a test concentration of 0.10 mg./cc.

(20) O (2 nitrophenyl) 4 methoxyacetophenone oxime, M.P. 1l11l3 C., fromisopropyl" alcohol, was prepared as in Example A(1) by heating on asteam bath for two hours a stirred mixture of the sodium salt of 4-methoxyacetophenone oxime and 2-chloronitrobenzene in a mixture oftetrahydrofuran and dimethyl sulfoxide.

(21) O (4 carbethoxyphenyl) 4 -'methoxyacetophenone oxime, M.P. 9092 C.,from isopropyl alcohol, was prepared as in Example A(1) by heating on asteam bath for three hours a stirred mixture of the sodium salt of4-methoxyacetophenone oxime and ethyl 4-fluorobenzoate in a mixture oftetrahydrofuran and dimethyl sulfoxide.

(22) O (2 trifluoromethylphenyl)acetophenone oxime, an oil, was preparedas in Example A(6) by heating on a steam bath a stirred mixture of thesodium salt of acetophenone oxime and 2-fluorobenzotrifluoride in amixture of tetrahydrofuran and dimethyl sulfoxide.

(23) O (4 nitro-2-trifluoromethylphenyl)acetone oxime, M.P. 87-90 C.,was prepared as in Example A(1) by stirring at room temperature for twohours the sodium salt of acetone oxime and4-chloro-3-trifluoromethylnitrobenzene in a mixture of tetrahydrofuranand dimethyl sulfoxide.

(B) CONVERSION OF O-PHENYL 'OXIMES TO BENZOFURANS (1)2-methyl-5-nitrobenzofuran.A 1.0 g. portion of O-(4-nitrophenyl)acetoneoxime was heated under reflux with ml. of 5 N ethanolic hydrogenchloride for ninety minutes. The reaction mixture was poured into waterand the product that separated was collected, washed with water, driedand recrystallized from isopropyl alcohol to yield 0.7 g. of2-methyl-5-nitrobenzofuran, M.P. 95-96 C. This reaction, using 1.0 g. ofO-(4-nitrophenyl)acetone oxime and ml. of 5 N ethanolic hydrogenchloride, was carried out by keeping the reaction mixture at about 56C., using an external refluxing acetone bath, for about sixteen hours.There was thus obtained 0.86 g. of 2- methyl-S-nitrobenzofuran, M.P.92-94 C. (unrecrystallized), mixed M.P.no depression. The structures ofthis and subsequent benzofurans produced by the process of the inventionwere confirmed by their infrared and nuclear magnetic resonance spectralanalyses.

2-methyl-5-nitrobenzofuran was also obtained from O-(4-nitrophenyl)acetone oxime by the following variations in theprocedure using different acids and solvents: In one, a mixture of 2.0g. of O-(4-nitrophenyl)acetone oxime and 10 ml. of 30% hydrogen bromidein acetic acid was heated on a steam bath for two hours and poured intowater whereupon the precipitated product was collected and dried toyield 1.6 g. of 2-methyl-5-nitrobenzofuran, M.P. 95-98 C. (mixed M.P.nodepression). In

the other, a mixture of 2.0 g. of O-(4-nitrophenyl)acetone oxime and 8ml. of trifluoroactic acid was heated on a steam bath for two hours andpoured into water; the product that separated was collected andrecrystallized from isopropyl alcohol-water, using decolorizingcharcoal, to yield 1.0 g. of 2-methyl-S-nitrobenzofuran, M.P. 9397 C.(mixed M.P.-no depression).

2-methyl-5-nitrobenzofuran was converted to S-amino- 2-methylbenzofuranand the latter to 5-acetamido-2- methylbenzofuran as follows: To 2 g. of2-methyl-5- nitrobenzofuran in 50 ml. of hot ethanol was added 2 ml. of100% hydrazine hydrate followed by slow addition of Raney nickel. Theresulting suspension was heated thirty minutes on a steam bath, thecatalyst was filtered off and the filtrate was concentrated in vacuo.The residual oil was taken up in ether and the ether solution treatedwith a solution of hydrogen chloride in ether. The resulting precipitatewas collected to give 1.5 g. of 5- amino-2-methylbenzofuranhydrochloride, M.P. 224- 226 C. with decomposition. A solutioncontaining 4 g. of 5-amino-2-methylbenzofuran and 3.1 g. of aceticanhydride was heated one hour on a steam bath and poured into water.After the aqueous mixture had been allowed to stand overnight, thecrystalline product was collected and recrystallized from isopropylalcohol to yield 2.4 g. of 5-acetamido-Z-methylbenzofuran, M.P. 135-137"C. S-acetamido-2-methylbenzofuran was found to have in vitrobacteriostatic activity against Escherichia coli and Proteus vulgariseach at a test concentration of 0.20 mg./ cc. This compound also wasfound to cause 45% inhibition of carrageenin-induced local foot edema infaster rats at 100 mg./ kg. orally.

(2) 5,7-dinitro-2-methylbenzofuran, 0.9 g., M.P. 163- 165 C., fromacetone-isopropyl alcohol, was prepared as in Example B(l) using 4.8 g.of O-(2,4-dinitrophenyl)- acetone oxime, ml. of 4.8 N ethanolic hydrogenchloride and a reflux period of about eighteen hours.

(3) 5-nitro-2-phenylbenzofuran, 11.1 g., M.P. 158- 161 C., was preparedas in Example B(l) using 13.0 g. of O-(4-nitrophenyl)acetophenone oxime,100 ml. of 4.81 N ethanolic hydrogen chloride and a reflux period ofabout two hours. 5-nitro-2-phenylbenzofuran was found to have in vitrobacteriostatic activity against Staphylococcus aureus, Pseudomonasaeruginosa, Escherichia coli and Proteus vulgaris at test concentrationsof 0.10, 0.075, 0.075 and 0.075 mg./cc. respectively. 5-nitro-2-phenylbenzofuran also was found to cause 30% inhibition ofcarrageenin-induced local foot edema in fasted rats at 100 mg./kg.orally.

(4) 2-methyl-7-nitrobenzofuran, 5.5 g., M.P. 10ll03 C., from n-heptane,was prepared following the procedure described above in Example B(l)using 15.5 g. of O-(2- nitrophenyl)acetone oxime, ml. of. 7.5 Nethanolic hydrogen chloride and a reflux period of one hour. 2-methyl-7-nitrobenzofuran was found to cause 31% inhibition ofcarrageenin-induced local foot edema in fasted rats at 100 mg./kg.orally.

(5) Ethyl 2 methyl S-nitro-7-benzofurancarboxylate, 3.9 g., M.P. 142l43C., from ethyl acetate, was prepared as in Example B(l) using 8.9 g. ofO-(Z-carboxy- 4-nitrophenyl)acetone oxime, 100 ml. of 7.9 N ethanolichydrogen chloride and a refiux period of two hours. The product wasextracted from the reaction mixture with methylene dichloride andrecrystallized from ethyl acetate. Ethyl2-methyl-5-nitro-7-benzofurancarboxylate was found to have in vitrobacteriostatic activity against Escherichia coli at a test concentrationof 0.15 mg./ cc.

(6) 2-methyl-7-nitro 5 trifiuoromethylbenzofuran, 1.6 g., M.P. 86-88 C.,from isopropyl alcohol, was prepared as in Example B( 1) using 11.6 g.of O-(2-nitro-4-trifluoromethylphenyl)acetone oxime in 50 ml. ofabsolute ethanol, 100 ml. of 4.8 N ethanolic hydrogen chloride and areflux period of about fifteen hours after the reaction mixture had beensaturated with hydrogen chloride. The product was obtained from thereaction mixture byevaporating 01f the ethanol, extracting with ether,removing the ether, and recrystallizing from isopropyl alcohol.

(7) 2-methyl-5-trifluoromethylbenzofuran.The intermediateO-(4-trifluoromethylphenyl)acetone oxime was prepared as in Example A(1)using the sodium salt of acetone oxime and 4-fluorobenzotrifluoride(16.4 g.) in a mixture of tetrahydrofuran and dimethyl sulfoxide and areflux period of three hours. The crystalline O-(4-trifluoromethylphenyl)acetone oxime was heated on a steam bath as in ExampleB(l) with 200 ml. of 8 N ethanolic hydrogen chloride for two hours. Thereaction mixture was poured into water, the aqueous mixture extractedwith ether, and the extract distilled in vacuo to yield 11.0 g. ofZ-methyI-S-trifluoromethylbenzofuran, B.P. 98 C., at 22 mm., M.P. 30 C.2-methyl-S-trifluoromethylbenzofuran was found to have in vitrobacteriostatic activity against Staphylococcus aureus at a testconcentration of 0.20 mg./ cc. This compound also was found to cause 34%inhibition of carrageenin-induced local foot edema in fasted rats atmg./ kg. orally.

(8) 5-cyano-Z-methylbenzofuran, M.P. 7678 C., was prepared as in ExampleB(l) using 1.7 g. of O-(4-cyanophenyl)acetone oxime in 20 ml. ofabsolute ethanol, 1.3 ml. of 8.0 N ethanolic hydrogen chloride, and areflux period of four hours. The product was obtained by evaporating theethanol from the reaction mixture, extracting with ether, removing theether, and recrystallizing from ethanol-water.

(9) 1,2,3,4 tetrahydro-8-nitrodibenzofuran.A mixture containing 8 g. ofO-(4-nitrophenyl)cyclohexanone oxime and 50 ml. of ethanolic hydrogenchloride was refluxed for three hours and allowed to cool. Theprecipitate was collected, washed successively with water and isopropylalcohol, and recrystallized from isopropyl alcohol to yield 6.4 g. of1,2,3,4-tetrahydro-8-nitrodibenzofuran, M.P. 144-147 C. This compoundwas found to have in vitro bacteriostatic activity against Escherichiacoli and Pseudomonas aeruginosa at test concentrations of 0.15 and 0.10mg./cc. respectively.

(10) 2 chloro 5,6,7,8 tetrahydrobenzofuro[2,3 b] pyridine, M.P. 9395 C.,was prepared as in Example B(9) using 18.5 g. ofO-(-chloro-2-pyridyl)cyclohexa' none oxime, 75 ml. of 5 N ethanolichydrogen chloride, and a reflux period of two hours. This product wasfound to have in vitro bacteriostatic activity against Pseudomonasaeruginosa at a test concentration of 0.15 mg./ cc. This compound alsowas found to cause 25% inhibition of carrageenin-induced local footedema in fasted rats at 100 mg./kg. orally.

(l1) 2,3-dimethyl-5-nitrobenzofuran.A mixture containing 5.6 g. ofO-(4-nitrophenyl)-2-butanone oxime and 50 ml. of 4.5 N ethanolichydrogen chloride was heated on a steam bath for two hours and thenpoured into water. The precipitated product was collected andrecrystallized from isopropyl alcohol to yield 1.5 g. of 2,3-dimethyl-S-nitrobenzofuran, M.P. 112-114 C. The filtrate yielded 0.9 g.of material, 70-73 C., which was shown by nuclear magnetic resonancespectral analysis to be a 60-40 mixture of 2-ethyl-5-nitrobenzofuran and2,3-dimethyl-S-nitrobenzofuran.

(l2) 2 benzoyloxy 1,2,3,4-tetrahydro-8-nitrodibenzofuran.A suspension of12 g. of 4-[(4-nitrophenoxy) imino]cyclohexyl benzoate in 100 ml. ofacetic acid saturated with hydrogen chloride was warmed until the soliddissolved and the resulting solution was heated on a steam bath forthree and one-half hours. The reaction mixture was then poured into oneliter of a mixture of ice and water. The solid that separated wascollected, Washed with water, recrystallized from absolute ethanol anddried in vacuo at 60 C. overnight (about sixteen hours) to yield 7.5 g.of 2-benzoyloxy-1,2,3,4-tetrahydro-8-nitrodibenzofuran, M.P. 15 6158 C.A further recrystallization from acetonitrile raised the melting pointto 157-159" C. The foregoing preparation can also be run using propionicacid or isobutyric acid in place of acetic acid as the solvent.2-benzoyloxy-l,2,3,4-tetrahydro-8-nitrodibenzofuran was found to cause28% inhibition of carrageenin-induced local foot edema in fasted rats at200 mg./kg. orally. Also, this compound was found to have in vitrobacteriostatic activity against Escherichia coli and Pseudomonasaeruginosa each at a test concentration of 0.10 mg./cc.

(13) 2 phenyl 5-trifluoromethylbenzofuran.-A mixture containing 7.7 g.of O-(4-trifluoromethylphenyl)acetophenone oxime and 75 ml. of 8 Nhydrogen chloride in ethanol was heated under reflux for two hours andthen poured into water. The solid that separated was collected andrecrystallized from n-hexane to yield 6.4 g. of 2-phenyl-5-trifluoromethylbenzofuran, M.P. l24135.5 C. This compound wasfound to have in vitro bacteriostatic activity against Staphylococcusaureu and Proteus vulgaris at test concentrations of 0.050 and 0.075mg./cc. respectively.

(14) Ethyl Z-methyl-5-nitrobenzofuran-3-acetate.-To a solutioncontaining 7.5 g. of tert-butyl levulinate oxime in 100 ml. of drydimethylformamide was added 4.5 g. of potassium tert-butoxide. To theresulting yellow solution was added 5 .6 g. of 4-fluoronitrobenzene inabout ml. of dimethylformamide whereupon an exothermic reaction raisedthe temperature of the reaction mixture to about 4550 C. The reactionmixture was stirred at room temperature for about ninety minutes andthen poured into 600 ml. of water. After the aqueous mixture had beenextracted with ether, the aqueous mixture was saturated with sodiumchloride and extracted again with ether. The combined ether extractswere washed with water, dried, treated with decolorizing charcoal andfiltered, and evaporated in vacuo to yield, as an oil, tert-butylO-(4-nitrophenyl)levulinate oxime which was converted to the henzofuranwithout further purificaiton. A small portion of said oily product wasrefluxed in ethanolic hydrogen chloride for about ninety minutes. Thehot reaction mixture was filtered to remove the precipitated ammoniumchloride which was washed with absolute ethanol. The filtrate yielded acrystalline product which was collected, washed with water andrecrystallized from ethanol to yield the crystalline product, ethyl2-methyl-5-nitrobenzofuran- 3-acetate, M.P. 114116 C.

(15) 7-chloro-2-methyl-5-nitrobenzofuran.A mixture containing 1 g. ofO-(2-chloro-4-nitrophenyl)acetone oxime and 15 ml. of 7 N ethanolichydrogen chloride was heated on a steam bath for two hours. The ethanolwas evaporated off in vacuo and water was added to the residualmaterial. The solid was collected, washed with water, and recrystallizedfrom isopropanol alcohol to yield 0.4 g. of7-chloro-2-methyl-5-nitrobenzofuran, M.P. 119- 121 C.

16) N,N-dimethyl-2-phenyl 5 benzofuransulfonamide, M.P. 166-168 C., frombenzene-isopropyl alcohol, was prepared as in Example B(l) using 1.0 g.of O-(4- N,N dimethylsulfamylphenyl)acetophenone oxime, ethanolichydrogen chloride and a reflux period of three hours. This compound wasfound to have in vitro bacteriostatic activity against Staphylococcusaureus, Escherichia coli and Proteus vulgaris each at a testconcentration of 0.075 mg./cc.

(17) N,N-dimethyl-2-(4-methoxyphenyl) 5 benzofuransulfonamide, 5.7 g.,M.P. 215-217 C., from dimethylformamide-absolute ethanol, was preparedas in Example B(l) using 8 g. ofO-(4-N,N-dimethylsulfarnylphenyl)-4-methoxyacetophenone oxime, 75 ml. of8.8 N ethanolic hydrogen chloride and 55 ml. of absolute ethanol and areflux period of two hours. This compound was found to have in vitrobacteriostatic activity against Escherichia coli at a test concentrationof 0.10 mg./cc.

(18) 2-phenyl 7 -trifluoromethylbenzofuran, 5.4 g., M.P. 4952 C., fromn-pentane after distilling at C. at 0.1 mm., was prepared as in ExampleB(l) using 12 g. of O-(Z-trifluoromethylphenyl)acetophenone oxime, 100ml. of 8 N ethanolic hydrogen chloride and a reflux period of threehours. The product was extracted with ether after the reaction mixturewas poured into water and then distilled under reduced pressure afterdrying the ether extract and removing the ether. 2-phenyl-7-trifiuoromethylbenzofuran was found to have in vitro bacteriostaticactivity against Staphylococcus aureus and Pseudomonas aeruginosa attest concentrations of 0.050 and 0.10 mg./cc. respectively.

19) Ethyl Z-phenyl-S-benzofurancarboxylate, 5.9 g., M.P. Ill-113 C.,from n-heptane (twice), was prepared as in Example B(l) using 6.0 g. ofO-(4-carbethoxyphenyl)acetophenone oxime, 50 ml. of ethanolic hydrogenchloride and a reflux period of three hours. This compound was found tohave in vitro bacteriostatic activity against Escherichia coli, Proteusvulgaris and PseudonLOnaS aeruginosa each at a test concentration of0.10 mg./cc.

(20) Ethyl 2-(4-methoxyphenyl) 5 benzofurancarboxylate, 12.7 g., M.P.131-l32 C., from isopropyl alcohol, was prepared as in Example B(l)using 16.5 g. O-(4-carbethoxyphenyl)-4-methoxyacetophenone oxime, 100ml. of 8.8 N ethanolic hydrogen chloride and a reflux period of twohours.

The above ethyl ester was converted into its Z-diethylaminoethyl esteras follows: To a solution containing 6.3 g. of ethyl2-(4-methoxyphenyl)-5-benzofurancarboxylate in 300 m1. of benzene wasadded 6 g. of 2-diethylaminoethanol followed by a trace (about 50 mg.)of sodium hydride. The resulting mixture was heated on a steam bath foreight hours. The benzene was distilled off in vacuo and the remainingmaterial was treated with water. The insoluble product was collected,washed with water and taken up in ether. Addition of a solution ofhydrogen chloride in ether precipitated the hydrochloride of the basicester. The hydrochloride was recrystallized first from isopropyl alcoholand then from dimethylformamide to yield 5.2 g. of 2-diethylaminoethyl2-(4-methoxyphenyl)- benzofuran-S-carboxylate hydrochloride, M.P. 225226C. This compound was found to have in vitro bacteriostatic activityagainst Staphylococcus aureus at a test concentration of 0.0125 mg./cc.

(21) 2-(4-methoxyphenyl)-7-nitrobenzofuran, 14.1 g., M.P. 122-124 C.,from absolute ethanol containing a small quantity of n-hexane, wasprepared as in Example B( 1) using 20 g. ofO-(Z-nitrophenyl)-4-methoxyacetophenone oxime, 200 ml. of 8.8 Nethanolic hydrogen chloride and a reflux period of three hours.

The above 7-nitrobenzofuran was converted into the corresponding7-aminobenzofuran as follows: To a suspension of 7.9 g. of2-(4-methoxyphenyl)-7-nitrobenzofuran in 200 ml. of absolute ethanol wasadded in small portions 6 g. of hydrazine hydrate and 4 g. of Raneynickel over a period of ninety minutes. The reaction mixture was thenheated for ninety minutes on a steam bath, the Raney nickel filteredoff, and the filtrate cooled. The precipitated product was collected,dried in vacuo at 60 C. overnight to yield 5.1 g. of7-amino-2-(4-methoxyphenyl)benzofuran, M.P. l49151 C.

(22) 2 methyl 5 phenylsulfonylbenzofuran, 4.9 g., M.P. l01-l03 C., fromisopropyl alcohol, was prepared as in Example B(l) using 7 g. ofO-(4-phenylsulfonylphenylacetone oxime, 50 ml. of 5 N ethanolic hydrogenchloride and a reflux period of two hours. After the reaction mixturehad been poured into water, the product was extracted from the aqueousmixture with methylene dichloride.

(23) 2-methyl-5-nitro-7-trifluoromethylhenzofuran, 5.9 g., M.P. 75-77C., from isopropyl alcohol, was prepared as in Example B(l) using 16 g.of O(2-trifluor0- methyl-4-nitrophenyl)acetone oxime, 100 ml. of 5 Nethanolic hydrogen chloride and a reflux period of four hours. After thereaction mixture had been poured into water, the product was extractedfrom the aqueous mixture with ether.

(24) 5-acetyl-Z-methylbenzofiuran, M.P. 62-66 C.,

12 from ethanol, was prepared as in Example B(l) using 0.8 g. ofO-(4-acetylphenyl)acetone oxime, 1 m1. of 7.9 N ethanolic hydrogenchloride and a reflux period of one hour.

(25) 2-methyl-S-nitrobenzofuran is also obtained following the procedureof Example B(l) by heating O-(4- nitrophenyl)acetone oxime in ethanolunder reflux using in place of hydrogen chloride a corresponding molarequivalent quantity of sulfuric acid, boron trifluoride etherate,methanesulfonic acid or p-toluenesulfonic acid.

The subject matter which the applicant regards as his invention isparticularly pointed out and distinctly claimed as follows. I claim:

1. A compound selected from the group consisting of O(4-cyanophenyl)acetone oxime, O (4-acetylphenyl) acetone oxime,O-(4-N,N-dimethylsulfamylphenyl)acetophenone oxime,O-(6-chloro-2-pyridyl)cyclohexanone oxime, 4-[(4-nitrophenoxy)imino]cyclohexyl benzoate, O-(4-phenylsulfonylphenyl)acetone oxime and O-(4-N,N-dimethylsulfamylphenyl)-4-methoxyacetophenone oxime.

2. 4-benzoyloxycyclohexanone oxime.

References Cited UNITED STATES PATENTS 3,209,008 9/1965 Poziomek et al.260-2949 HENRY R. JILES, Primary Examiner A. L. ROTMAN, AssistantExaminer US. Cl. X.R.

@3 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,#81, 9 4 4- Dated December 2, 1969 lnventofly') Aram Mooradian It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

1 Column 1, line 16, "and" should read --an-; line "posses" should read--possess--; line 71, l-[ should read 4-[ Column 2, line 15, "N, shouldread N- line 1 "N, should read N- line 22, "methoxphenyl" should read-methoxyphenyl--; line #1, "illustrate" should read "illustrated".Column 4, line 9, "pyridylcyclo" shoul read --pyridyl)cyclo-; line 33,"an" should read --and--; l 33, recrqrscallize" should read--recrystallized--. Column line 5 4, hexane should read --hexanoneline56, "123" should read -12}. 5--. Column 7, line 65, faster should re--fasted. Column 11, line 21, "phenylacetone" should read ""Penyl)acetone--.

SIGNED IND SEALED JUN 2 197 W J! m: E.

Eamanmmm-Ir. 253 of meat: AneatingoOfficer

